Many individuals in our Veteran population, especially the Vietnam era cohort, suffer from dementia-related cognitive impairment. This number is expected to increase as the population of Veterans age. Developing effective treatment strategies is of the upmost importance, as this impairment places a huge burden on the Veterans themselves, their caregivers, and the resources of the Department of Veterans Affairs. Repetitive transcranial magenetic stimulation (rTMS) is a promising treatment strategy, that utilizes electromagnetics to noninvasively activate cortical cells and restore cognitive functioning. It is thought that this process increases neurotrophic signaling throughout the brain, and could potentially increase the integrity of brain structures sensitive to a loss in neurotrophic factors, especially those structures that declince early in the course of Alzhiemer's disease (AD). This proposal aims to improve our understanding of the neurochemistry of cognitive decline, and subsequently, rehabilitation from rTMS treatment using both human and animal models. We will assess changes in the neurotrophic factor Brain-Derived Neurotrophic Factor (BDNF) as a result of AD and how rTMS treatment influences BDNF signaling. The role of this measure will be related to cognitive performance in both humans and mice. We will first assess the extent of changes in BDNF signaling in a mouse model of AD, and then we will implement an rTMS system for mice to increase BDNF in the brains of these mice. This system will be used to test the brain neurochemistry of changes in cognitive function in AD. Utilization of a mouse model will allow us to comprehensively investigate neurochemistry in a controlled experimental settting. Specifically, we will measure alterations in the signaling pathway of BDNF in a mouse model of AD for both rTMS-treated and control mice. We will also determine if rTMS can be utilized to prevent AD pathology in these mice by providing long-term treatment, and measuring both biochemical changes and cognitive performance. Finally, BDNF will be measured in blood samples from humans with cognitive impairment either treated with rTMS or a sham in order to related biochemistry to changes in human cognitive dysfunction. Exploratory research on key proteins from cerebral spinal fluid and plasma in humans will pave the way for future funding opportunities in the biochemistry of cognition. Results from this proposal will provide valuable insight into the biochemical mechanisms of cognitive decline. This research will also identify key biomarkers that can be related to cognitive performance and be utilized as concrete measures of treatment outcome. The combination of biochemical and cognitive measurements on both humans and animals provides an innovative, multi-faceted approach that can be directly translated into medical treatments for our Veterans.